Abstract
Backgrounds: In autoimmune rheumatic diseases (ARDs), the levels of inflammatory mediators are increased and microglia may be activated, resulting in an inflammatory state and the degeneration of dopaminergic neurons. We investigated the association between ARDs and Parkinson disease (PD).
Methods: We identified ARD patients through the Taiwan National Health Insurance Research Database from 2001 to 2012. From the general population, we randomly selected a comparison cohort that was frequency-matched by age (in 5-year increments), sex and index year. We analysed the risk of PD, stratified by sex, age and comorbidities, by using a Cox regression model.
Results: The risk of PD was 1.37 times greater in ARD patients than in controls after adjustment for age, sex, and comorbidities. ARD subgroups, such as the rheumatoid arthritis and Sjogren syndrome (SS) cohorts, were associated with a significantly higher risk of PD (adjusted hazard ratio [HR], 1.14; 95% confidence interval [CI], 1.03–1.2 and adjusted HR, 1.56; 95% CI, 1.35–1.79, respectively). Furthermore, primary and secondary SS patients had significantly higher risks of PD (adjusted HR, 1.58; 95% CI, 1.32–1.88 and adjusted HR, 1.53, 95% CI, 1.23–1.90, respectively).
Conclusions: The risk of PD was significantly higher in the ARD patients. Prospective studies are needed to confirm whether ARDs indeed increase the risk of PD.
Introduction
Following Alzheimer disease, Parkinson disease (PD) is the second most common neurodegenerative disorder, with an incidence of 14 per 100,000 person-years in developed countries [Citation1]. PD is a movement disorder that clinically exhibits rigidity, bradykinesia, postural instability and tremors, as well as several nonmotor features, including dementia and depression [Citation2,Citation3]. The main pathological finding associated with the motor deficits of PD is the degeneration of dopaminergic neurons in the pars compacta of the substantia nigra (SN), leading to a deficiency of dopamine in the striatum. The aetiology of PD may involve genetic or environmental factors or even interactions among aging-related factors, genetic predisposition and environmental exposure [Citation4]. The mechanisms of PD may include defective handling of proteins, mitochondrial dysfunction, oxidative stress and inflammation. One hypothesis is that inflammatory mediators activate immune cells in the brain (microglia), which may cause or contribute to the degeneration of neurons [Citation5]. Despite intensive research, the cause of the neuronal loss in Parkinson’s disease is poorly understood. Neuroinflammatory mechanisms might contribute to the cascade of events leading to neuronal degeneration [Citation6].
Autoimmune diseases form a range of disorders from organ-specific (e.g. Hashimoto’s thyroiditis) to systemic disorders with multiorgan involvement. Disorders that mainly, but not exclusively, affect joints and muscles are grouped together as the autoimmune rheumatic diseases (ARDs) and include rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), Sjogren syndrome (SS), progressive systemic sclerosis (PSS), polymyositis (PM), dermatomyositis (DM), vasculitides (including polyarteritis nodosa, Kawasaki disease, hypersensitivity angiitis, Wegener granulomatosis, giant cell arteritis and Takayasu arteritis) and Behcet disease are chronic diseases characterized by progressive and systemic inflammation. Patients with ARDs, such as RA and SLE, produce chronically high concentrations of inflammatory mediators over long periods of time [Citation6], and these patients are hypothesized to have an increased risk of developing neurodegenerative diseases such as PD [Citation7–9]. This hypothesis is supported by postmortem studies on the brains of Parkinsonian patients; these studies revealed increased levels of proinflammatory mediators and apoptosis-related proteins in the striatal dopaminergic regions of the brain [Citation10–12]. However, whether the inflammation is a cause or consequence of PD remains unclear. Recently, higher serum levels of the inflammatory mediator interleukin-6 during a 5-year interval before diagnosis were associated with an increased risk of PD [Citation13]. In addition, epidemiological studies have suggested that the regular use of anti-inflammatory drugs may be associated with a decreased risk of PD [Citation14–16].
To address the possible relationship between immunologically induced inflammation and PD, we examined associations between ARDs and the risk of PD in a nationwide, population-based case-control study in Taiwan.
Methods
Data source
The data source was the National Health Insurance Research Database (NHIRD) of Taiwan, which covers inpatient and ambulatory care claims from 2001 to 2012. The National Health Insurance (NHI) program of the Bureau of National Health Insurance (BNHI) includes all the healthcare data of original claims from more than 99% of the population in Taiwan (23.74 million) [Citation17]. It is a comprehensive computerized database, including all medical claims for ambulatory care services and hospitalization and can therefore facilitate a nationwide, population-based cohort study. The BNHI performs a routine validation of the diagnoses by reviewing the original medical charts of all patients. The NHIRD has established a registry system for catastrophic illnesses. The completeness and accuracy of the NHI claims databases were assured by the aforementioned agencies. The study was approved by the Institutional Review Board of Taipei Medical University (approval number: N201509007). The study was conducted in accordance with the approved guidelines. Informed consent of study participants was not required because the data set used in this study consists of de-identified secondary data released for research purposes. Numerous general population based studies have been successfully conducted using these databases [Citation18–21].
Study design and cohort definition
We conducted a retrospective cohort study using NHI database and conducted matched cohort analyses for incident PD among adults with incident ARDs (ARDs cohort) as compared with adults without ARDs randomly selected from the general population using NHIRD (comparison cohorts). We created incident ARDs cohorts with cases diagnosed for the first time between January 2002 and December 2012. Our study definition of middle-aged ARDs consisted of: individuals ≥45 years of age; identified from the catastrophic illness registry in the NHIRD. In Taiwan, patients with ARDs are eligible for a catastrophic illness certificate after a rheumatology specialist makes the diagnosis based on clinical manifestations, laboratory data and the international criteria, that certification requires precise fulfilment of related classification criteria as follows: American College of Rheumatology (ACR) 1997 revised criteria for systemic lupus erythematosus (SLE, ICD-9-CM: 710.0) [Citation22]; American Rheumatism Association 1987 revised criteria for rheumatoid arthritis (RA, ICD-9-CM: 714.0) [Citation23]; ACR criteria for systemic sclerosis (SSc, ICD-9-CM: 710.1) [Citation24]; American–European Consensus Group 2002 revised criteria for Sjogren’s syndrome (ICD-9-CM: 710.2) [Citation25]; Bohan and Peter 1975 criteria for polymyositis and dermatomyositis (ICD-9-CM: 710.3) [Citation26,Citation27]; International Study Group 1990 criteria for Behçet disease (ICD-9-CM: 136.1) [Citation28]; and ACR 1990 criteria for temporal arteritis (ICD-9-CM: 443.1) [Citation29], granulomatosis polyangiitis (GPA, ICD-9-CM: 446.4) [Citation30] and Takayasu arteritis (ICD-9-CM: 446.7) [Citation31]. Thus, the catastrophic illness patient data are highly accurate and reliable [Citation20,Citation21]. A brief summary of the ARDs is shown in .
Table 1. Brief summary of the autoimmune rheumatic diseases and ICD-9 code.
Outcomes and comorbidities
The primary outcome was the occurrence of PD(ICD-9-CM 332). A person was considered to have a new onset of PD only if the condition occurred in an inpatient setting or was noted in three or more outpatient visits. All cases were followed from the index date to the date of PD diagnosis by neurologist, withdrawal from the insurance programme, censoring because of death, or 31 December 2012. Covariates consisted of potential risk factors for PD assessed during the year before the index date. These comorbid conditions were coronary artery disease (ICD-9-CM 410–414), stroke (ICD-9-CM 430–438), hyperlipidaemia (ICD-9-CM 272), hypertension (ICD-9-CM 401–405), diabetes (ICD-9-CM 250) and head injury (ICD-9-CM 850-854, 959.01).
Statistical analysis
We statistically analysed the middle-aged ARD and control groups. The examined variables were sex, age, age group and comorbidities. The chi-square test and t-test were used to compare the categorical and continuous variables, respectively, between the ARD and comparison groups. A Cox proportional hazards regression model was used to compare the risk of PD between the ARD and comparison groups. A hazard ratio (HR) of >1 indicated that patients with ARDs had a higher risk of PD than did the comparison group. We calculated the incidence rate ratio (IRR), HR, and 95% confidence interval (CI) in an analysis stratified by sex, age and comorbidities. Furthermore, we analysed the IRR, HR and 95% CI for the ARD, RA, SLE, SS, primary SS, secondary SS and other ARD cohorts stratified by age (<65 years and ≥65 years). Cumulative incidence plots prepared using the Kaplan–Meier method were used to compare the ARD and control; RA and control; primary SS, secondary SS and control; and SLE and control cohorts. In this study, a p value of <.05 was considered statistically significant. All analyses were performed using SAS software, version 9.2 (SAS Institute, Cary, NC).
Results
Baseline characteristics of the study population. A total of 34,606 cases of middle-aged ARDs and 138,424 matched control cases from the defined period of interest were selected from the NHIRD. Demographic characteristics and baseline comorbidities are shown in The dominant sex was female (77.3%). The majority of the patients were younger than 65 years (70%). The prevalence of comorbidities was greater in the ARD cohort (all p values were <.0001). Follow-up year in ARD patients is 6.00 ± 5.71years and 6.40 ± 6.21 years in comparison group.
Table 2. Baseline characteristics of the ARD and age- and sex-matched control groups.
Incidence rate of PD in ARDs and non-ARDs. The incidence rate and adjusted HR of the ARD and non-ARD cohorts are shown in . During the observation period, 2285 and 694 patients in the non-ARD and ARD cohorts developed PD, respectively. The overall incidence rate of PD was 30% higher in the ARD cohort than in the non-ARD cohort (33.44 vs. 25.79 per 10,000 person-years), with an adjusted HR of 1.30 (95% CI = 1.13–1.34) after adjustment for age, sex, and comorbidities. The incidence rate of PD was 1.24 times greater in women with ARDs than in women without ARDs (31.34 vs. 24.08 per 10,000 person-years), with an adjusted HR of 1.26 (95% CI = 1.18–1.35). The age-specific incidence rate of PD increased with age in both cohorts. Among subjects aged 75 years or older, the risk of PD was higher in those with ARDs than in those without ARDs (adjusted HR = 1.30, 95% CI = 1.10–1.54).
Table 3. Incidence of PD and cox model results for the ARD and comparison groups.
PD risk based on multivariate Cox proportional hazard analysis. In , compared with the non-ARD cohort, the RA and SS cohorts were associated with a significantly higher risk of PD (adjusted HR = 1.14, 95% CI = 1.03–1.28 and adjusted HR = 1.56, 95% CI = 1.35–1.79, respectively). In addition, female patients with RA and SS had a significantly higher risk of PD. Furthermore, SS was divided into primary and secondary SS. shows that patients with SS had a significantly higher risk of PD (adjusted HR = 1.56, 95% CI = 1.35–1.79); also shows that patients with primary and secondary SS had significantly higher risks of PD (adjusted HR = 1.58, 95% CI 1.32–1.88 and adjusted HR = 1.53, 95% CI = 1.23–1.90, respectively). Among patients younger or older than 65 years, the adjusted HR of PD was also significantly greater in both primary and secondary SS patients.
Table 4. Incidence of PD and cox model results for the subgroups of the ARD and comparison groups.
Cumulative incidences of PD in ARDs and non-ARD cohort. shows the comparative cumulative incidence of PD for the ARD and non-ARD cohorts. The incidence of PD (log rank test, p < .001) was significantly greater in patients with ARDs than in those without ARDs. ) shows the comparative cumulative incidence of PD for the subgroups of the ARD and non-ARD cohorts. The incidence of PD (log rank test, p < .001) was significantly greater in the subgroups of the ARD cohort, except in the SLE subgroup, than in the non-ARD cohort.
Figure 1. Cumulative incidence of Parkinson disease in the autoimmune rheumatic disease and comparison groups.
Discussion
To the best of our knowledge, this is the first nationwide population-based study to evaluate the relationship between middle-aged ARDs and PD. In this study, the overall incidence rate of PD was 30% higher in the ARD cohort than in the non-ARD cohort, with an adjusted HR of 1.23 after adjustment for age, sex and comorbidities. The subgroups of the ARD cohort, such as the RA and SS cohorts, also had a significantly higher risk of PD. We therefore postulate that middle-aged ARDs increase the risk of PD.
By contrast, Rugbjerg et al. identified no overall association between autoimmune diseases and PD in a population-based case–control study [Citation32]. The heterogeneity of these results may reflect the underlying differences in study design and methodology. The study of Rugbjerg et al. was a case–control trial, while our study is a retrospective study. The existence of a shared immunopathogenesis between ARDs and PD, which are inflammatory and neurodegenerative diseases, respectively, is under question. Currently, neuroinflammation is being considered in the debate on the physiopathogenesis of PD [Citation33]. Evidence of autoimmune involvement in PD was recently discussed [Citation34]. Tumour necrosis factor-alpha (TNF-α), a proinflammatory cytokine involved in SS and other systemic diseases, showed high titres in the blood, cerebrospinal fluid and striatum of patients with PD [Citation35]. Recent autopsy, genetics and molecular imaging results suggest that inflammation plays a role in the neurodegenerative process [Citation35]. Therefore, inflammation in patients with ARDs may be a key factor in the development of PD.
To date, only a few incidental observations of extrapyramidal signs have been described in patients with SS. An exhaustive bibliographic search identified only 14 cases of PD associated with PSS [Citation36]. Our study revealed that the incidence of PD in patients with SS (aged >45 years) was 2.5% (215/8422). This finding may be due to an autoimmune process directed against the basal ganglia. The pathogenic roles of anti-SSA and anti-SSB remain controversial [Citation37]. High titres of anti-beta2-glycoprotein IgG were identified in the serum of patients who had PD associated with PSS [Citation38]. This autoantibody is strongly associated with anticardiolipin (aCL) antibodies, antiphospholipid syndrome and thromboembolic phenomena, but its role in the pathogenesis of PD in SS is still unclear. These patients may present with a subtype of SS in which aCL antibodies directly attack the basal ganglia and cause Parkinsonian symptoms. In addition, the direct toxicity of T cells has been considered after the discovery of lymphocytic infiltration on histological sections of biopsied brain injury tissue [Citation39].
Our study showed that the RA cohort had a significantly higher risk of PD. Therefore, we propose the existence of a pathogenetic link between RA and PD. The coexistence of RA and PD has been mentioned by a few authors [Citation7,Citation40]. Kogure et al. examined a 52-year-old woman with RA who developed PD [Citation39]. Ertan et al. reported that the frequency of PD among patients with RA was 2.3% [Citation40]. Upregulation of major histocompatibility complex molecules can occur in PD brains [Citation41], and the levels of beta2-microglobulin, the light chain of the major histocompatibility complex, can be increased in the striata of patients with PD [Citation42]. Subsequently, the accumulation of inflammatory cytokines in the SN of patients with PD further supports a role of chronic inflammation [Citation43]. Indeed, inflammation is a key etiopathogenic factor for RA and the hypothetical processes of PD [Citation44,Citation45]. Inflammatory mediators are chronically produced in RA, and these mediators may cause or contribute to the degeneration of neurons. The key role of TNF in RA is clear, but the mechanisms by which TNF moderates the neuroinflammatory and neurotoxic effects leading to nigrostriatal degeneration are not yet well understood. TNF levels in the brains of healthy adults are generally very low and are mainly produced by neurons. By contrast, TNF levels in the SN of postmortem brains of patients with PD are higher. Studies also suggest that dopaminergic neurons in the SN are utterly sensitive to TNF [Citation46,Citation47]. A recently published review stated that adhesion molecules, TNF, interleukin-1β and interleukin-6, and nitric oxide are elevated in patients with PD, and these substances amplify and mediate the irreversible destruction of dopaminergic neurons in the SN [Citation48].
Epidemiological evidence has shown that chronic treatment with non-steroidal anti-inflammatory drugs (NSAIDs) reduces the risk of PD [Citation48]. These data might be explained by the protective effect of long-term NSAID treatment in RA patients [Citation32]. Rugbjerg et al. observed a 30% decrease in the risk of PD among RA patients [Citation32]. Laboratory investigations have also shown that NSAIDs reduce the formation of neurotoxic molecules [Citation49] and inhibit the activation of transcription factors controlling the expression of genes involved in immune and inflammatory functions [Citation50]. However, in the present investigation, no data were available on the use of NSAIDs by the study population.
The present study revealed that patients with SLE were not associated with a significantly higher risk of PD, whereas the association of PD with immunological diseases such as SLE has been reported [Citation9]. Overt PD is rare in adult-onset SLE [Citation51]. PD may be an extremely unusual manifestation of central nervous system lupus. The underlying pathophysiological sequence leading to overt PD in patients with SLE is yet to be clarified, but it is probably complex and multifactorial. A thorough review by Moore and Lisack [Citation52] discussing the immunopathogenesis of neurological dysfunction in SLE refers to a combination of direct immune-mediated effects, including immune complexes, autoantibodies, cytokines and activated lymphocytes and indirect effects, including vasculopathy, coagulopathy, cardiac emboli and bleeding disturbances. By contrast, Liu et al. observed an inverse association between a diagnosis of SLE and the risk of subsequent Parkinson disease [Citation53].
The strength of our study is the use of population-based data that are highly representative of the general population. However, there were some limitations. First, the database did not include the smoking status and the report of each examination, which are important for both ARDs and PD. In relation to PD, smoking is one of the most extensively studied lifestyle behaviours. An inverse association between smoking and PD has been reported [Citation54]. Our study could not accurately determine the relative effect of smoking on ARDs and PD. Furthermore, because the examination reports were not available, the disease activity and the severity of ARDs or PD were unknown, which prevent a deeper analysis of the mechanism. Additional prospective studies should be conducted to confirm whether disease activity and the severity of ARDs increase the risk of PD. Second, in this study, the diagnoses were mainly based on ICD in the data set. However, the diagnoses were based on the ICD in the catastrophic illness registration. The peer-review validation mechanism made the diagnoses reliable. For the diagnoses of PD, a very conservative strategy was taken (1) all diagnoses were made by neurologist and (2) only those diagnosed during admission or presented in three or more outpatient visit were counted. Although this strategy might miss some cases, those defined as PD would be homogenous and reliable. Third, most of the subjects in our study were Taiwanese, which limited the generalization of the result to patients with other ethnicities. Finally, this study revealed the association but no further analyses about the mechanism were done. Except for the lack of some information mentioned above, the pathogenesis and medication differed between these ADRs. We left further analyses for each specific autoimmune disease in the following studies which are undergoing now.
In conclusion, this nationwide, population-based, retrospective cohort study revealed that patients with middle-aged ARDs (except SLE and vasculitis) have an increased risk of PD. Subgroups of the ARD cohort, such as the RA and SS cohorts, were also associated with a significantly higher risk of PD. In addition, patients with primary and secondary SS had a significantly higher risk of PD. Future studies are needed to elucidate the underlying immunologic mechanisms and to translate them into clinical therapeutic options.
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All authors declare no conflicts of interest for this work.
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References
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